WO2011143296A1 - Pharmaceutical formulations comprising 1 - (beta-d-glucopyranosyl) - 2 -thienylmethylbenzene derivatives as inhibitors of sglt - Google Patents

Pharmaceutical formulations comprising 1 - (beta-d-glucopyranosyl) - 2 -thienylmethylbenzene derivatives as inhibitors of sglt Download PDF

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Publication number
WO2011143296A1
WO2011143296A1 PCT/US2011/036038 US2011036038W WO2011143296A1 WO 2011143296 A1 WO2011143296 A1 WO 2011143296A1 US 2011036038 W US2011036038 W US 2011036038W WO 2011143296 A1 WO2011143296 A1 WO 2011143296A1
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present
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formulation
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PCT/US2011/036038
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English (en)
French (fr)
Inventor
Wenhua Wang
Todd Outwin
Thomas C. Joseph
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Janssen Pharmaceutica Nv
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Priority to BR112012028857-1A priority Critical patent/BR112012028857B1/pt
Priority to AU2011250909A priority patent/AU2011250909A1/en
Priority to CN2011800236428A priority patent/CN102883726A/zh
Priority to EP11721616.8A priority patent/EP2568988B1/en
Priority to SG2012083184A priority patent/SG185525A1/en
Priority to KR1020127031880A priority patent/KR101931209B1/ko
Priority to JP2013510272A priority patent/JP6227406B2/ja
Priority to ES11721616.8T priority patent/ES2596291T3/es
Priority to SI201130932A priority patent/SI2568988T1/sl
Priority to MX2012013090A priority patent/MX339570B/es
Priority to RS20160815A priority patent/RS55202B1/sr
Priority to LTEP11721616.8T priority patent/LT2568988T/lt
Priority to CA2799204A priority patent/CA2799204C/en
Priority to EA201291217A priority patent/EA022365B1/ru
Priority to DK11721616.8T priority patent/DK2568988T3/en
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Priority to UAA201214097A priority patent/UA110207C2/ru
Publication of WO2011143296A1 publication Critical patent/WO2011143296A1/en
Priority to IL222858A priority patent/IL222858B/en
Priority to CR20120626A priority patent/CR20120626A/es
Priority to SM201600338T priority patent/SMT201600338B/it
Priority to HRP20161231TT priority patent/HRP20161231T1/hr
Priority to CY20161101017T priority patent/CY1118093T1/el

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    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/2022—Organic macromolecular compounds
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
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    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention relates to novel pharmaceutical compositions comprising a compound of Formula (I), a prodrug thereof, or a pharmaceutically acceptable salt thereof, disclosed herein, that can be used in the treatment of diabetes mellitus, obesity, diabetic complications, and related diseases.
  • WO 2005/012326 discloses a class of compounds that are inhibitors of sodium-dependent glucose transporter (SGLT) and therapeutic uses for such compounds such as the treatment of diabetes, obesity, diabetic complications, and the like.
  • SGLT sodium-dependent glucose transporter
  • WO 2005/012326 discloses the compound 1 -( -D-glucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene).
  • the present invention provides a novel pharmaceutical composition of compounds of Formula (I), a prodrug thereof, or a pharmaceutically acceptable salt thereof, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with sodium- dependent glucose transporter using such pharmaceutical compositions.
  • One aspect of the present invention features an orally administrable pharmaceutical formulation comprising
  • Ri is halo, cyano, optionally substituted lower alkyl, or optionally substituted lower alkoxyl
  • R 2 is optionally substituted aryl, or optionally substituted heterocyclyl
  • the compound of formula (I) is present in an amount within the range of from about 1 % to about 80% by weight;
  • the diluent or filler is present in an amount within the range of from about 10% to about 95% by weight;
  • the disintegrant if present, is present in an amount within the range of from about 0.1 % to about 20% by weight;
  • the binder if present, is present in an amount within the range of from about 0.1 % to about 20% by weight;
  • the lubricant if present, is present in an amount within the range of from about 0.1 % to about 5% by weight, all of the above % by weight being based on the weight of the formulation.
  • the compound of Formula (I) is a compound of Formula (l-S) as described herein.
  • the present invention is directed to an orally administrable pharmaceutical formulation comprising a compound of Formula (I) as described herein in combination with a bioavailability-promoting agent.
  • the bioavailability-promoting agent increases the bioavailability of the compound and includes excipients known in the formulation of pharmaceuticals.
  • formulating a compound of Formula (I) with the bioavailability-promoting agent results in improved measurable bioavailability of the compound upon administration of the formulation.
  • the present invention is further directed to a bioavailability- promoting agent that includes a composition of excipients, such as binders, fillers, disintegrants, lubricants or combinations thereof.
  • the formulation of the present invention is a solid oral dosage form that provides for an increased bioavailability of the compound included therein as compared to an oral suspension including the compound in the same amount as the solid oral dosage form.
  • Figure 1A and B provides linear and logarithmic plasma concentration profiles of compound of Formula (l-S) following oral administration of various formulations of compound of Formula (l-S) in dogs.
  • Figure 2 provides plasma concentration profiles of compound (l-S) following oral administration of various formulations of compound of Formula (l-S) in human subjects.
  • the present invention is directed in part to an orally administrable
  • the compound of formula (l-S) is present in an amount within the range of from about 1 % to about 80% by weight;
  • the diluent or filler is present in an amount within the range of from about 10% to about 95% by weight;
  • the disintegrant if present, is present in an amount within the range of from about 0.1 % to about 20% by weight;
  • the binder if present, is present in an amount within the range of from about 0.1 % to about 20% by weight;
  • the lubricant if present, is present in an amount within the range of from about 0.1 % to about 5% by weight, all of the above % by weight being based on the weight of the formulation.
  • the present invention is directed to an orally administrable pharmaceutical formulation comprising
  • % by weight is based on the weight of the formulation.
  • the compound of Formula (l-S) may also be referred to as 1 -( ⁇ - ⁇ - glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene).
  • the compound of formula (l-S) is the hemihydrate of the compound of Formula (l-S), also referred to as 1 -( ⁇ - ⁇ - glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene) hemihydrate.
  • the invention is directed to a pharmaceutical composition as described herein for use in the manufacture of a pharmaceutical dosage form for oral administration to a mammal in need of treatment,
  • the invention is directed to a method of therapy of the human or non-human animal body that comprises administering to said body a therapeutically effective dose of a pharmaceutical composition described herein.
  • the invention is directed to a pharmaceutical package suitable for commercial sale comprising a container, an oral dosage form as described herein, and associated with said package written matter non-limited as to whether the dosage form can be administered with or without food.
  • administering means providing a drug to a patient in a manner that is pharmacologically useful.
  • Patient or “subject” means an animal, preferably a mammal, more preferably a human, in need of therapeutic intervention.
  • Dosage form means one or more compounds in a medium, carrier, vehicle, or device suitable for administration to a patient.
  • Oral dosage form means a dosage form suitable for oral administration.
  • Dose means a unit of drug. Conventionally, a dose is provided as a dosage form. Doses may be administered to patients according to a variety of dosing regimens. Common dosing regimens include once daily orally (qd), twice daily orally (bid), and thrice daily orally (tid).
  • “Terminal half-life” (t1 ⁇ 2) is calculated as 0.693/k, wherein "k” means the apparent elimination rate constant, estimated by linear regression of the log- transformed plasma concentration during the terminal log-linear elimination phase.
  • the plasma half-life of a drug (t1 ⁇ 2) is the time necessary to halve the plasma concentration, for example to decrease from 100 to 50 mg/L.
  • the knowledge of the half-life is useful for the determination of the frequency of administration of a drug (the number of intakes per day) for obtaining the desired plasma
  • the half-life of a particular drug is independent of the dose administered. In certain exceptional cases, it varies with the dose: it can increase or decrease according to, for example, the saturation of a mechanism (elimination, catabolism, binding to plasma proteins etc).
  • AUC Absolute under the curve
  • AUC is the area as measured under a plasma drug concentration curve, also termed plasma concentration profile.
  • the AUC is specified in terms of the time interval across which the plasma drug concentration curve is being integrated, for instance AUCstart-finish.
  • AUCo-48h refers to the AUC obtained from integrating the plasma concentration curve over a period of zero to 48 hours, where zero is conventionally the time of administration of the drug or dosage form comprising the drug to a patient.
  • AUCt refers to area under the plasma concentration curve from hour 0 to the last detectable
  • AUCinf refers to the AUC value extrapolated to infinity, calculated as the sum of AUCt and the area extrapolated to infinity, calculated by the concentration at time t (C t ) divided by k. (If the t1 ⁇ 2 value was not estimable for a subject, the mean t1 ⁇ 2 value of that treatment was used to calculate AUCinf.).
  • AUCinf obtained over several patients or multiple administrations to the same patient on different occasions with sufficient washout in between dosings to allow drug levels to subside to pre-dose levels, etc., following a single administration of a dosage form to each patient.
  • C means the concentration of drug in blood plasma, or serum, of a subject, generally expressed as mass per unit volume, typically nanograms per milliliter. For convenience, this concentration may be referred to herein as “drug plasma concentration", “plasma drug concentration” or “plasma concentration”.
  • the plasma drug concentration at any time following drug administration is referenced as Ctime, as in C 9h or C 24n , etc.
  • a maximum plasma concentration obtained following administration of a dosage form obtained directly from the experimental data without interpolation is referred to as C max .
  • the average or mean plasma concentration obtained during a period of interest is referred to as C av g or Cmean - "Mean, single dose, maximum plasma concentration C ma x" means the mean C ma x obtained over several patients or multiple administrations to the same patient with sufficient washout in between dosing to allow drug levels to subside to pre-dose levels, etc., etc., following a single administration of a dosage form to each patient.
  • “Plasma concentration profile” refers to the curve obtained by plotting plasma concentration of the drug compound versus time. Usually, the convention is that the zero point on the time scale (conventionally on the x axis) is the time of administration of the drug compound or dosage form comprising the drug compound to a patient.
  • Mean time to maximum plasma concentration is the mean time elapsed from administration to a patient of a dosage form comprising a drug to the time at which the C ma x for that drug is obtained over several patients or multiple administrations to the same patient with sufficient washout in between dosing to allow drug levels to subside to pre-dose levels, etc., following a single
  • the bioavailability indicates the percentage of the administered drug, which arrives in the central compartment. It is generally measured by comparing the AUC obtained after intravenous administration and after oral administration, for example. After intravenous administration, the AUC obtained corresponds to a bioavailability, which, by definition, is 100%; after oral administration, the AUC corresponds at best to an identical bioavailability. It is generally lower, sometimes null. In contrast, in this application bioavailability is indicated by the maximum plasma concentration C ma x reached after administration of the drug. A higher C max of a drug dosage form is indicative of better drug bioavailability via administrating this dosage form.
  • the compartment indicates the fictitious volume in which a drug would be distributed. It can correspond or not to a real volume, for example the volume of blood called first or central compartment, or the whole body except blood, called second compartment.
  • the central compartment typically includes the plasma and in addition those tissues or parts in tissues in which drug concentrations rapidly come to equilibrium with the plasma.
  • the real anatomical sectors in which the drug is distributed at different concentrations are represented by one, two, rarely three virtual compartments where the concentration of the drug is regarded as
  • halo means chlorine, bromine, iodine, and fluorine, and chlorine and fluorine are preferable.
  • alkyl or "alkyl group” means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms.
  • the straight chain or branched chain alkyl group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkyl group having 1 to 4 carbon atoms is more preferable.
  • alkyl group examples thereof are methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group, 4,4-dimethylpentyl group, octyl group, 2,2,4- trimethylpentyl group, nonyl group, decyl group, and various branched chain isomers thereof.
  • the alkyl group may optionally and independently be substituted by one to five substituents as listed below, if necessary.
  • Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups.
  • the alkoxy may be optionally and independently be substituted with one to five, preferably one to three substituents defined below.
  • alkylene group or "alkylene group” means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms.
  • the straight chain or branched chain alkylene group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkylene group having 1 to 4 carbon atoms is more preferable. Examples thereof are methylene group, ethylene group, propylene group, trimethylene group, etc. If necessary, the alkylene group may optionally be substituted in the same manner as the above- mentioned "alkyl group”.
  • alkylene groups as defined above attach at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle together with the carbon atoms to which they are attached, and may optionally be substituted by one or more substituents defined below.
  • alkenyl group means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond.
  • Preferable alkenyl group is a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, and the straight chain or branched chain alkenyl group having 2 to 4 carbon atoms is more preferable.
  • Examples thereof are vinyl group, 2-propenyl group, 3-butenyl group, 2-butenyl group, 4-pentenyl group, 3- pentenyl group, 2-hexenyl group, 3-hexenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group, 3- undecenyl group, 4-dodecenyl group, 4,8,12-tetradecatrienyl group, etc.
  • the alkenyl group may optionally and independently be substituted by 1 to 4
  • alkenylene group means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond.
  • the straight chain or branched chain alkenylene group having 2 to 6 carbon atoms is preferable, and the straight chain or branched chain alkenylene group having 2 to 4 carbon atoms is more preferable. Examples thereof are vinylene group, propenylene group, butadienylene group, etc.
  • the alkylene group may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • alkenylene groups as defined above attach at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle (e.g., a fused benzene ring) together with the carbon atoms to which they are attached, and may optionally be substituted by one or more substituents defined below.
  • alkynyl group means a straight or branched monovalent hydrocarbon chain having at least one triple bond.
  • the preferable alkynyl group is a straight chain or branched chain alkynyl group having 2 to 6 carbon atoms, and the straight chain or branched chain alkynyl group having 2 to 4 carbon atoms is more preferable.
  • Examples thereof are 2-propynyl group, 3-butynyl group, 2- butynyl group, 4-pentynyl group, 3-pentynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3- nonynyl group, 4-decynyl group, 3-undecynyl group, 4-dodecynyl group, etc.
  • the alkynyl group may optionally and independently be substituted by 1 to 4
  • cycloalkyl group means a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and the monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms is more preferable.
  • examples thereof are a monocyclic alkyl group and a bicyclic alkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, etc.
  • These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary), and the condensed saturated hydrocarbon ring and the condensed unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • cycloalkylidene group means a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and the monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms is preferable. Examples thereof are a monocyclic alkylidene group and a bicyclic alkylidene group such as cyclopropyl idene group, cyclobutylidene group, cyclopentylidine group,
  • cyclohexylidene group etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkylidene group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary), and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • cycloalkenyl group means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having at least one double bond.
  • the preferable cycloalkenyl group is a monocyclic unsaturated hydrocarbon group having 4 to 7 carbon atoms. Examples thereof are monocyclic alkenyl groups such as cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkenyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary), and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • cycloalkynyl group means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms, and having at least one triple bond.
  • the preferable cycloalkynyl group is a monocyclic unsaturated hydrocarbon group having 6 to 8 carbon atoms. Examples thereof are monocyclic alkynyl groups such as cyclooctynyl group, cyclodecynyl group. These groups may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkynyl group may optionally and independently be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary), and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • aryl group means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms.
  • phenyl group examples thereof are phenyl group, naphthyl group (including 1 -naphthyl group and 2-naphthyl group). These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the aryl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO 2 within the ring, if necessary), and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • saturated monocyclic heterocyclic ring means an unsaturated hydrocarbon ring containing 1 -4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the preferable one is a 4- to 7-membered saturated or unsaturated hydrocarbon ring containing 1 -4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazole can be preferably used.
  • the "unsaturated monocyclic heterocyclic ring" may optionally and independently be substituted by 1 -4 substituents as mentioned below, if necessary.
  • saturated fused heterobicyclic ring means hydrocarbon ring comprised of a saturated or a unsaturated hydrocarbon ring condensed with the above mentioned unsaturated monocyclic heterocyclic ring where said saturated hydrocarbon ring and said unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO, or SO 2 within the ring, if necessary.
  • the "unsaturated fused heterobicyclic ring” includes, for example, benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, dihydroisoquinoline, etc. Further, the "heterocyclic ring” also includes possible N- or S-oxides thereof.
  • heterocyclyl means a monovalent group of the above- mentioned unsaturated monocyclic heterocyclic ring or unsaturated fused heterobicyclic ring and a monovalent group of the saturated version of the above- mentioned unsaturated monocyclic heterocyclic or unsaturated fused
  • heterocyclyl may optionally and
  • alkanoyl group means a formyl group and ones formed by binding an "alkyl group” to a carbonyl group.
  • substituted refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • each group includes, for example, a halogen atom (fluorine, chlorine, bromine), a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cydoalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, an alkenylcarbonyl group
  • alkynylcarbonyl group a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, an arylcarbonyl group, a hetero-cyclylcarbonyl group, an alkoxy-carbonyl group, an alkenyloxy-carbonyl group, an alkynyloxy-carbonyl group, a cycloalkyloxy-carbonyl group, a cycloalkenyl-oxy-carbonyl group, a cyclo- alkynyl-oxycarbonyl group, an aryloxycarbonyl group, a hetero-cyclyloxycarbonyl group, an alkanoyloxy group, an alkenyl-carbonyloxy group, an alkynyl- carbonyloxy group, a cycloalkyl-carbonyloxy group, a cycloalkenyl-carbonyloxy group, a cycloalkyny
  • alkynylsulfinyl group a cycloalkyl-sulfinyl group, a cycloalkenylsulfinyl group, a cycloalkynyl-sulfinyl group, an arylsulfinyl group, a heterocyclyl-sulfinyl group, an alkyl-sulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl group, a cycloalkenyl-sulfonyl group, a cycloalkynylsulfonyl group, an aryl-sulfonyl group, and a heterocyclylsulfonyl group.
  • Each group as mentioned above may optionally be substituted by these substituents.
  • haloalkyl group such as a haloalkyl group, a halo-lower alkyl group, a haloalkoxy group, a halo-lower alkoxy group, a halophenyl group, or a
  • haloheterocyclyl group mean an alkyl group, a lower alkyl group, an alkoxy group, a lower alkoxy group, a phenyl group or a heterocyclyl group (hereinafter, referred to as an alkyl group, etc.) being substituted by one or more halogen atoms, respectively.
  • Preferable ones are an alkyl group, etc. being substituted by 1 to 7 halogen atoms, and more preferable ones are an alkyl group, etc. being
  • hydroxyalkyl group a hydroxy-lower alkyl group, a hydroxyalkoxy group, a hydroxy-lower alkoxy group and a hydroxyphenyl group mean an alkyl group, etc., being substituted by one or more hydroxy groups.
  • Preferable ones are an alkyl group, etc., being substituted by 1 to 4 hydroxy groups, and more preferable ones are an alkyl group, etc., being substituted by 1 to 2 hydroxy groups.
  • an alkoxyalkyl group a lower alkoxyalkyl group, an alkoxy-lower alkyl group, a lower alkoxy-lower alkyl group, an alkoxyalkoxy group, a lower alkoxyalkoxy group, an alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy group, an alkoxyphenyl group, and a lower alkoxyphenyl group means an alkyl group, etc., being substituted by one or more alkoxy groups.
  • Preferable ones are an alkyl group, etc., being substituted by 1 to 4 alkoxy groups, and more preferable ones are an alkyl group, etc., being substituted by 1 to 2 alkoxy groups.
  • arylalkyl and arylalkoxy as used alone or as part of another group refer to alkyl and alkoxy groups as described above having an aryl substituent.
  • lower used in the definitions for the formulae in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless defined otherwise. More preferably, it means a straight or branched carbon chain having 1 to 4 carbon atoms.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • prodrug means an ester or carbonate, which is formed by reacting one or more hydroxy groups of the compound of the Formula (I) with an acylating agent substituted by an alkyl, an alkoxy or an aryl by a conventional method to produce acetate, pivalate, methylcarbonate, benzoate, etc.
  • the prodrug includes also an ester or amide, which is similarly formed by reacting one or more hydroxy groups of the compound of the Formula (I) with an a-amino acid or a ⁇ -amino acid, etc. using a condensing agent by a conventional method.
  • the prodrug includes also ether, which is similarly formed by reacting one or more hydroxy groups of the compound of the Formula (I) with a condensing agent via a conventional method.
  • “Pharmaceutically acceptable” means molecular entities and
  • compositions that are of sufficient purity and quality for use in the formulation of a composition or medicament of the present invention. Since both human use (clinical and over-the-counter) and veterinary use are equally included within the scope of the present invention, a formulation would include a composition or medicament for either human or veterinary use.
  • pharmaceutically acceptable salt refers includes, for example, a salt with an alkali metal such as lithium, sodium, potassium, etc.; a salt with an alkaline earth metal such as calcium, magnesium, etc.; a salt with zinc or aluminum; a salt with an organic base such as ammonium, choline,
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • a salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.
  • a salt with an acidic amino acid such as aspartic acid, glutamic acid, etc.
  • the compound of Formula (I) of the present invention also includes a mixture of stereoisomers, or each pure or substantially pure isomer.
  • the present compound may optionally have one or more asymmetric centers at a carbon atom containing any one of substituents. Therefore, the compound of the Formula (I) may exist in the form of enantiomer or diastereomer, or a mixture thereof.
  • the present compound of Formula (I) may exist in the form of geometric isomerism (cis-compound, trans-compound), and when the present compound of Formula (I) contains an unsaturated bond such as carbonyl, then the present compound may exist in the form of a tautomer, and the present compound also includes these isomers or a mixture thereof.
  • the starting compound in the form of a racemic mixture, enantiomer or diastereomer may be used in the processes for preparing the present compound.
  • the present compound is obtained in the form of a diastereomer or enantiomer, they can be separated by a conventional method such as chromatography or fractional crystallization.
  • the present compound of Formula (I) includes an intramolecular salt, hydrate, solvate or polymorphism thereof.
  • the formulation of the present invention is useful for treating or delaying the progression or onset of a sodium-dependent glucose transporter mediated disorder.
  • the formulation of the present invention is useful for treating or delaying the progression or onset of diabetes mellitus, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis, or hypertension.
  • the formulation of the present invention is useful in the treatment or the prophylaxis of diabetes mellitus (type 1 and type 2 diabetes mellitus, etc.), diabetic complications (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) or obesity, or is useful in the treatment of postprandial
  • Ri as shown in Formula (I) is a halogen atom, or a lower alkyl group; and F3 ⁇ 4 as shown in Formula (I) phenyl is optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono-or di-lower alkylamino group, a carbamoyl group, and a mono-or di-lower alkylcarbamoyl group.
  • Preferably drug compounds of Formula (I) used in the disclosed formulation typically possess slight to poor water solubility in their crystalline or amorphous form and hence poor bioavailability, but the present invention is not necessarily limited to compounds with little to no water solubility.
  • Preferred representative compounds for use in the formulations of the present invention include 1 -( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene), or a prodrug or a pharmaceutically acceptable salt thereof.
  • the compound for use in the formulations of the present invention is 1 -( -D-glucopyranosyl)-4-methyl-3-[5-(4- fluorophenyl)-2-thienylmethyl]benzene) hemihydrate.
  • the 1 -( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene), or a prodrug or a pharmaceutically acceptable salt thereof is included in the formulation of the present invention in an amount of from about 25 mg to about 600 mg, preferably from about 50 mg to about 400 mg.
  • the 1 -( -D-glucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), or a prodrug or a pharmaceutically acceptable salt thereof is included in the formulation of the present invention in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg.
  • the 1 -( ⁇ - ⁇ - glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), or a prodrug or a pharmaceutically acceptable salt thereof is included in the formulation of the present invention in an amount of about 100 mg or about 300 mg.
  • the 1 -( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)- 2-thienylmethyl]benzene) is in the hemihydrate
  • the 1 -( -D-glucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene) hemihydrate is preferably included in the formulation in an amount of about 25.5 mg, about 51 mg, about 102 mg, about 204 mg, or about 306 mg, preferably in an amount of about 102 mg or about 306 mg.
  • the compound is formulated into oral dosage forms suitable for administration to patients in need thereof.
  • the oral dosage form may be provided in any pharmaceutically acceptable solid dosage form.
  • the solid dosage form includes, for example, solid preparation such as tablets, pills, granules, capsules, powders and others. More preferably, the solid dosage form is an oral tablet or capsule formulation. Most preferably the solid dosage form is an oral tablet.
  • the formulation includes a filler or diluent in the amount of about 10% to about 95% by weight of the formulation, preferably from about 25% to about 90% by weight of the formulation, more preferably from about 30% to about 50% by weight of the formulation or from about 35% to about 45% by weight of the formulation.
  • the formulation includes a disintegrant in the amount of about 0.1 % to about 20% by weight of the
  • the formulation includes a binder in the amount of about 0.1 % to about 20% by weight of the formulation, preferably from about 0.1 % to about 10% by weight of the formulation, more preferably from about 0.5% to about 5% by weight of the formulation or from about 1 % to about 4% by weight of the formulation.
  • the formulation includes a lubricant in the amount of about 0.1 % to about 5% by weight of the formulation, preferably from about 0.1 % to about 2% by weight of the formulation, more preferably from about 0.5% to 2% by weight of the formulation or 0.5% to 1 .5% by weight of the formulation.
  • the formulation optionally includes a surfactant in the amount of about 0% to about 10% by weight of the formulation, preferably from about 0% to about 5% by weight of the formulation.
  • the solid dosage forms may comprise the compound in combination with various pharmaceutically acceptable excipients, and preferably the dosage form is adapted to provide increased bioavailability of the compound in a manner to obtain the desired clinical effect through oral administration to the patient.
  • the bioavailability promoting agent of the present invention includes any combination of the excipients described herein such that the formulation provides for the increase bioavailability of the compound included the formulation.
  • the bioavailability promoting agent includes two or more excipients described herein.
  • compositions are known in the art and can be provided according to considerations of desired functionality and process ability.
  • Roles for the excipients in the oral dosage form include but are not limited to fillers, binders, disintegrants, release controlling agents, glidants, lubricants, coatings and the like.
  • the dosage form preferably comprises a disintegrant in an amount as noted herein.
  • a controlled or sustained release formulation of the compound is desired. Such a formulation can be achieved by varying the amounts, concentrations and ratios of certain release controlling polymers.
  • the formulation of the present invention includes the compound in an amount of about 1 % to about 80%, preferably from about 5% to about 60% by weight of the formulation, more preferably from about 40% to about 60% by weight of the formulation or about 45% to about 55% by weight of the formulation.
  • one or more of the dosage forms can be administered.
  • an oral release formulation is provided in tablet form comprising about 100 mg of 1 -( ⁇ - ⁇ - glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, lactose anhydrous, and magnesium stearate.
  • an oral release formulation in tablet form comprising about 300 mg of 1 -( ⁇ - ⁇ - glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, lactose anhydrous, and magnesium stearate.
  • an oral release formulation in tablet form comprising about 102 mg of 1 -( ⁇ - ⁇ - glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene) hemihydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, lactose anhydrous, and magnesium stearate.
  • an oral release formulation in tablet form comprising about 306 mg of 1 -( ⁇ - ⁇ - glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene) hemihydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, lactose anhydrous, and magnesium stearate.
  • Fillers or diluents for use in the formulations of the present invention include fillers or diluents typically used in the formulation of pharmaceuticals.
  • fillers or diluents for use in accordance with the present invention include but are not limited to sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cycludextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like.
  • the filler or diluent is lactose, microcrystalline cellulose, or combination thereof.
  • microcrystalline cellulose selected from the group consisting of Avicel® types: PH101 , PH102, PH103, PH105, PH 1 12, PH1 13, PH200, PH301 , and other types of microcrystalline cellulose, such as silicified
  • lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flo, directly compressible anhydrous lactose, and modified lactose monohydrate.
  • the filler or diluent is a combination of
  • microcrystalline cellulose and lactose microcrystalline cellulose and lactose.
  • Binders for use in the formulations of the present invention include binders commonly used in the formulation of pharmaceuticals.
  • Examples of binders for use in accordance with the present invention include but are not limited to cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl
  • methylcellulose, methylcellulose, and sodium carboxymethyl cellulose glycol
  • sucrose dextrose
  • corn syrup polysaccharides (including acacia, targacanth, guar, alginates and starch)
  • corn starch pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol,
  • the binding agent if present, is hydroxypropyl cellulose.
  • Disintegrants for use in the formulations of the present invention include disintegrants commonly used in the formulation of pharmaceuticals.
  • examples of disintegrants for use in accordance with the present invention include but are not limited to starches, clays, celluloses, alginates and gums and crosslinked starches, celluloses and polymers, combinations thereof and the like.
  • disintegrants include microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crosprovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodiumstarch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like.
  • the disintegrant if present, is a cross-linked cellulose, more preferably cross-linked sodium
  • Lubricants for use in the formulations of the present invention include lubricants commonly used in the formulation of pharmaceuticals.
  • examples of lubricants for use in accordance with the present invention include but are not limited to magnesium carbonate, magnesium laurylsulphate, calcium silicate, talc, fumed silicon dioxide, combinations thereof, and the like.
  • lubricants include but are not limited to magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof, and the like.
  • the lubricant if present, is magnesium stearate or stearic acid, more preferably magnesium stearate.
  • Surfactants for use in the formulations of the present invention include surfactants commonly used in the formulation of pharmaceuticals.
  • surfactants for use in accordance with the present invention include but are not limited to ionic-and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives,
  • MC methylcellulose
  • EEC ethylcellulose
  • HEC hydroxyethylcellulose
  • MHEC methyl hydroxyethylcellulose
  • HPMC hydroxypropyl methylcellulose
  • NaCMC sodium carboxymethylcellulose
  • the pharmaceutical formulations disclosed herein can further comprise antioxidants and chelating agents.
  • the pharmaceutical formulations can comprise butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), sodium metabisulfite, ascorbyl palmitate, potassium
  • disodium EDTA ethylenediamine tetraacetic acid; also known as disodium edentate
  • EDTA ethylenediamine tetraacetic acid
  • tartaric acid citric acid
  • citric acid monohydrate citric acid monohydrate
  • sodium sulfite sodium sulfite
  • the tablet or capsule of the invention has a protective outer layer.
  • the protective outer layer of the tablet or capsule can include from about 10% to about 95% of polymer based on the weight of the coating layer, and can be prepared employing conventional procedures.
  • the outer layer of the tablet or capsule includes from about 20% to about 90% of polymer based on the weight of the coating layer.
  • the formulation can contain at least one coating layer polymer and a coating solvent, for example, water, which is used for processing and removed by drying. Suitable examples of polymer for the coating layer include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, and starch.
  • the coating layer polymer is PVA. In another embodiment, the coating layer polymer is hydroxypropyl cellulose.
  • the coating can also optionally include a plasticizer of from about 0% to about 30% by weight, based on the weight of the coating layer. In one
  • the plasticizer is from about 15% to about 25% by weight of the coating layer.
  • Suitable plasticizers include, but are not limited to, triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin, and triaethyl citrate, for example.
  • the coating can also optionally include an anti- adherent or glidant such as talc, fumed silica, or magnesium stearate, for example.
  • an anti- adherent or glidant such as talc, fumed silica, or magnesium stearate, for example.
  • the coating can also optionally include an
  • opacifying agent such as titanium dioxide, for example.
  • the tablet may be further coated with a coating layer that provides cosmetic benefits to the dosage form.
  • a coating layer that provides cosmetic benefits to the dosage form.
  • such a coating helps to protect the tablets.
  • such coating comprises hydroxypropyl methylcellulose, polyethylene glycol, polydextrose, titanium dioxide, and triacetin.
  • such coating comprises hydroxypropyl methylcellulose 2910, polyethylene glycol 400, polydextrose, titanium dioxide, carnuba wax, and iron oxide yellow.
  • such a coating layer comprises
  • Opadry® II (white) in an amount of from about 0% to about 10% by weight of the tablet; in certain other embodiments in an amount of from about 0% to about 6% by weight of the tablet; and in still other embodiments in an amount of from about, 0% to about 3% by weight of the tablet; and in other embodiments from about 2 to about 4% by weight of the tablet.
  • therapeutic agent(s) suitable for combination with the formulations of the present invention include, but are not limited to, known therapeutic agents useful in the treatment of the aforementioned disorders associated with SGLT2 activity including: anti-diabetic agents; anti-hyperglycemic agents; hypolipidemic or lipid lowering agents; anti-obesity agents; anti-hypertensive agents and appetite suppressants.
  • the invention further provides a method for treating or delaying the progression or onset of diseases or disorders associated with SGLT2 activity comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of the pharmaceutical formulation of the invention and one or more of the following: anti-diabetic agent(s), anti-hyperglycemic agent(s); hypolipidemic or lipid lowering agent(s); anti-obesity agent(s); anti- hypertensive agent(s) and appetite suppressant(s).
  • anti-diabetic agent(s) anti-hyperglycemic agent(s); hypolipidemic or lipid lowering agent(s); anti-obesity agent(s); anti- hypertensive agent(s) and appetite suppressant(s).
  • the invention provides a method for treating type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of the pharmaceutical formulation of the invention and one or more anti-diabetic agent(s).
  • the invention provides a method for delaying the progression or onset of type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of the pharmaceutical formulation of the invention and one or more anti-diabetic agent(s).
  • the invention provides a method for treating or delaying the progression or onset of type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of the pharmaceutical formulation of the invention and one or more of the following: anti-hyperglycemic agent(s); hypolipidemic or lipid lowering agent(s); anti-obesity agent(s); anti-hypertensive agent(s) and appetite suppressant(s).
  • the invention provides a method for treating or delaying the progression or onset of type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the invention and an anti-hyperglycemic agent(s).
  • the invention provides a method for treating or delaying the progression or onset of type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the invention and a hypolipidemic agent(s).
  • the invention provides a method for treating or delaying the progression or onset of type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the invention and an anti-obesity agent(s).
  • the invention provides a method for treating or delaying the progression or onset of type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the invention and an anti-hypertensive agent(s).
  • the invention provides a method for treating or delaying the progression or onset of type II diabetes comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the invention and an appetite suppressant(s).
  • Suitable anti-diabetic agents for use in combination with the formulations of the present invention include, but are not limited to, biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide and glipizide), biguanide/glyburide combinations (e.g., Glucovance®),
  • biguanides e.g., metformin or phenformin
  • glucosidase inhibitors e.g., acarbose or miglitol
  • insulins including insulin secretagogues or insulin sensitizers
  • meglitinides e.g.,
  • thiazolidinediones e.g., troglitazone, rosiglitazone and pioglitazone
  • PPAR-alpha agonists e.g., troglitazone, rosiglitazone and pioglitazone
  • PPAR-gamma agonists e.g., PPAR-gamma agonists
  • PPAR alpha/gamma dual agonists e.g., glycogen phosphorylase inhibitors, inhibitors of fatty acid binding protein (aP2), glucagon- like peptide-1 (GLP-1 ) and other agonists of the GLP-1 receptor, and dipeptidyl peptidase IV (DPP4) inhibitors.
  • aP2 fatty acid binding protein
  • GLP-1 glucagon- like peptide-1
  • DPP4 inhibitors e.g., dipeptidyl peptidase IV
  • thiazolidinediones include, but are not limited to, MCC-555, faraglitazar, englitazone or darglitazone; isaglitazone, reglitazar, rivoglitazone, liraglutide , and (Z)-1 ,4-bis-4-[(3,5-dioxo-1 ,2,4-oxadiazolidin-2-yl- methyl)]phenoxybut-2-ene.
  • PPAR-alpha agonists examples include PPAR-alpha agonists, PPAR-gamma agonists and PPAR
  • alpha/gamma dual agonists include, but are not limited to, muraglitazar, peliglitazar, tesaglitazar AR-HO39242, GW-501516, and IRP297.
  • Suitable DPP4 inhibitors include, but are not limited to, sitigliptin and saxagliptin.
  • glucagon-like peptide-1 such as GLP-1 (1 -36) amide, GLP-1 (7-36) amide, GLP-1 (7- 37), exenatide, LY-315902, MK-0431 , liraglutide, ZP-10, and CJC-1 131 .
  • hypolipidemic/lipid lowering agents for use in combination with the formulations of the present invention include one or more MTP inhibitors, HMG CoA reductase inhibitors (such as e.g., mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, atavastatin, rosuvastatin), squalene synthetase inhibitors, fibric acid derivatives (such as e.g., fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, bile acid sequestrants, such as cholestyramine, colestipol and DEAE-Sephadex, as well as lipostabil), ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal NaVbile acid co-transporter inhibitors,
  • Suitable anti-hypertensive agents include, but are not limited to, beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,
  • beta adrenergic blockers calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and
  • renin inhibitors e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril
  • AT-1 receptor antagonists e.g., losartan, irbesartan, valsartan
  • ET receptor antagonists e.g., sitaxsentan, and atrsentan.
  • Suitable anti-obesity agents for use in combination with the formulations of the present invention include, but are not limited to, beta 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, thyroid receptor beta drugs, 5HT2C agonists; MCHR1 antagonists, such as Synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, NPY1 or NPY5
  • NPY2 and NPY4 modulators corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, 1 1 -beta-HSD-1 inhibitors, adinopectin receptor modulators, monoamine reuptake inhibitors or releasing agents, ciliary neurotrophic factors, BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, cannabinoid-1 receptor antagonists, and anorectic agents.
  • H3 modulators histamine receptor-3 (H3) modulators
  • 1 1 -beta-HSD-1 inhibitors 1 1 -beta-HSD-1 inhibitors
  • adinopectin receptor modulators monoamine reuptake inhibitors or releasing agents
  • ciliary neurotrophic factors BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, cannabinoid-1 receptor antagonists, and anorectic agents.
  • BDNF brain-derived neurotroph
  • lipase inhibitors that can be employed in combination with lipase inhibitors
  • formulations of the present invention include, but are not limited to, orlistat and ATL-962 (Alizyme).
  • Serotonin (and dopamine) reuptake inhibitors include, but are not limited to, BVT-933, sibutramine, topiramate and axokine.
  • Examples of monoamine reuptake inhibitors that can be employed in combination with the formulations of the present invention include, but are not limited to, fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.
  • Anorectic agents that can be employed in combination with the formulations of the present invention include, but are not limited to, topiramate, dexamphetamine, phentermine, phenylpropanolamine and mazindol.
  • the other therapeutic agent(s) can be used, for example, in the amounts indicated in the Physician's Desk Reference, or as otherwise known and used by one of ordinary skill in the art.
  • each of the compounds of the combination can be administered simultaneously or sequentially and in any order, and the components can be administered separately or as a fixed combination, in jointly therapeutically effective amounts, for example, in daily dosages as described herein.
  • a fixed combination of the invention can be prepared by mixing a dry granulation of the compound of Formula (I) or (l-S) or formulation of the invention and a dry granulation of the other therapeutic agent(s) and filling the mixture into capsules of desired size, shape, color, or other characteristics, or compressing to form tablets.
  • the formulations of the invention are prepared by making an admixture of the drug compound, and a bioavailability-promoting agent. Dissolving these components in a liquid solvent therefore and subsequently removing the solvent may affect this most straightforwardly.
  • the invention provides a process for the preparation of a
  • composition comprising: dissolving a drug
  • dosage forms in accordance with the embodiments depicted herein are manufactured by standard techniques.
  • the dosage form may be manufactured by the wet granulation technique.
  • the drug and carrier are blended using an aqueous or organic solvent, such as denatured anhydrous ethanol, as the granulation fluid.
  • the remaining ingredients can be dissolved in a portion of the granulation fluid, such as the solvent described above, and this latter prepared wet blend is slowly added to the drug blend with continual mixing in the blender.
  • the granulating fluid is added until a wet blend is produced, which wet mass blend is then forced through a
  • granules or powders of the drug layer compositions and push layer composition are sequentially placed in an appropriately-sized die with intermediate compression steps being applied to each of the first two layers, followed by a final compression step after the last layer is added to the die to form the trilayered core.
  • the intermediate compression typically takes place under a force of about 50-100 Newtons.
  • Final stage compression typically takes place at a force of 3500 Newtons or greater, often 3500-5000 Newtons.
  • the compressed cores are fed to a dry coater press, e.g., Kilian® Dry Coaterpress, and subsequently coated with the wall materials as described herein.
  • Pan coating may be conveniently used to provide the completed dosage form.
  • the wall-forming composition for the inner wall or the outer wall, as the case may be is deposited by successive spraying of the appropriate wall composition onto the compressed core accompanied by tumbling in a rotating pan.
  • a pan coater is used because of its availability at commercial scale. Other techniques can be used for coating the compressed core.
  • the wall is dried in a forced-air oven or in a temperature and humidity controlled oven to free the dosage form of solvent(s) used in the manufacturing. Drying conditions will be conventionally chosen on the basis of available equipment, ambient conditions, solvents, coatings, coating thickness, and the like.
  • one alternative technique uses an air-suspension procedure. This procedure consists of suspending and tumbling the compressed core in a current of air, until a coating is applied to the core.
  • the air-suspension procedure is described in U.S. Patent No. 2,799,241 ; in J. Am. Pharm. Assoc., Vol. 48, pp. 451 -459 (1959); and, ibid., Vol. 49, pp. 82-84 (1960).
  • the dosage form also can be coated with a Wurster® air-suspension coater using, for example, methylene dichloride methanol as a cosolvent for the wall forming material.
  • An Aeromatic® air-suspension coater can be used employing a cosolvent.
  • the drug and other ingredients comprising the drug layer are blended and pressed into a solid layer.
  • the layer possesses dimensions that correspond to the internal dimensions of the area the layer is to occupy in the dosage form, and it also possesses dimensions corresponding to the push layer, if included, for forming a contacting arrangement therewith.
  • the drug and other ingredients can also be blended with a solvent and mixed into a solid or semisolid form by conventional methods, such as ballmilling, calendering, stirring or rollnnilling, and then pressed into a preselected shape.
  • the compressed cores then may be coated with the inner wall material and the semipermeable wall material as described herein.
  • Another manufacturing process that can be used comprises blending the powdered ingredients in a fluid bed granulator. After the powdered ingredients are dry blended in the granulator, a granulating fluid, for example, polyvinylpyrrolidone in water, is sprayed onto the powders. The coated powders are then dried in the granulator. This process granulates all the ingredients present therein while adding the granulating fluid. After the granules are dried, a lubricant, such as stearic acid or magnesium stearate, is mixed into the granulation using a blender e.g., V- blender or tote blender. The granules are then pressed and coated in the manner described above.
  • a granulating fluid for example, polyvinylpyrrolidone in water
  • components comprise aqueous or inert organic solvents that do not adversely harm the materials used in the system.
  • the solvents broadly include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatics, aromatics, heterocyclic solvents and mixtures thereof.
  • Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethylacetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, nhexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloridenitroethane, nitropropane
  • tetrachloroethane ethyl ether
  • isopropyl ether cyclohexane, cyclooctane
  • benzene toluene, naphtha, 1 ,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts such as sodium chloride, calcium chloride, and the like, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichlo de and methanol.
  • Exemplary liquid carriers for the present invention include lipophilic solvents (e.g., oils and lipids), surfactants, and hydrophilic solvents.
  • Exemplary lipophilic solvents include, but are not limited to, Capmul PG-8, Caprol MPGO, Capryol 90, Plurol Oleique CC497, Capmul MCM, Labrafac PG, N-Decyl Alcohol, Caprol 10G10O, Oleic Acid, Vitamin E, Maisine 35-1 , Gelucire 33/01 , Gelucire 44/14, Lauryl Alcohol, Captex 355EP, Captex 500, Capylic/Caplic Triglyceride, Peceol, Caprol ET, Labrafil M2125 CS, Labrafac CC, Labrafil M20 1944 CS,
  • Captex 8277 Myvacet 9-45, Isopropyl Nyristate, Caprol PGE 860, Olive Oil, Plurol Oleique, Peanut Oil, Captex 300 Low C6, and Capric Acid.
  • Exemplary surfactants include, but are not limited to, Vitamin E TPGS, Cremophor (grades EL, EL-P, and RH40), Labrasol, Tween (grades 20, 60, 80), Pluronic (gradesL-31 , L-35, L-42, L-64, and L-121 ), Acconon S-35, Solutol HS-15, and Span (grades 20, and 80).
  • hydrophilic solvents for example, include, but are not limited to, Isosorbide Dimethyl Ether, Polyethylene Glycol (PEG grades 300, 400, 600, 3000, 4000, 6000, and 8000) and Propylene Glycol (PG).
  • Shaping may be effected by spray- drying the solution (to provide the product in particulate form), by evaporation of solvent from solution disposed in molds, by molding (e. g. injection molding), by extrusion and the like.
  • the product can be formed when hot and allowed to solidify on cooling.
  • the shaped product may likewise be produced in film or sheet form by evaporation or by pouring a heated mass onto a plate and
  • Tablets were prepared using the ingredients listed in Tables 1 .1 -1 .6 and the following procedure.
  • Hydroxypropyl cellulose and purified water were mixed to prepare the granulating solution.
  • the granulating solution was sprayed into the fluid bed to granulate the dry ingredients.
  • the dried granules were passed through a suitable mill fitted with an appropriate screen.
  • the milled granulation was placed in an appropriate blender and combined with screened magnesium stearate.
  • the mixture was blended for an appropriate period of time.
  • a suitable rotary tablet press was employed to compress the final blend into tablets.
  • the filmcoating powder was mixed with purified water to obtain the film-coating suspension.
  • the tablets were filmcoated in a suitable coating pan and dried.
  • the dogs received 10 mL of tap water to ensure delivery of the entire dose.
  • Blood samples of about 3 mL were collected via jugular venipuncture, or other suitable site, into K 2 EDTA tubes and placed on wet ice, at times of 0, 0.5, 1 , 2, 4, 8, 24, and 48 hours post initial dosing. Plasma was harvested by centrifugation, and frozen at -20 °C. All samples were placed in amber vials for protection from white light and were processed within two hours of collection.
  • Plasma samples were analyzed for plasma concentrations of drug compound 1 -( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene) by using a liquid chromatographic-triple quadruple mass spectrometric (LC-MS/MS) assay procedure with a lower limit of quantification of 50 ng/mL.
  • Plasma concentration data were electronically transferred to a
  • the WatsonTM LIMS computer system assigns a value of 0.00 to those concentrations below the lower limit of quantification.
  • the nanosuspension used as a control in the study included a 0.5%
  • Methocel ® suspension measured in weight percentage. Methocel ® is a
  • HPMC hydroxypropyl methylcellulose
  • bioavailability as indicated by AUC inf , following administration of the compound of the 100mg Tablet Formulation or the 25mg Tablet Formulation was higher than after the administration of the 5mg/mL nanosuspension.
  • the 400 mg tablet dose was achieved by administering two doses of the 200mg Tablet
  • the median time to maximum plasma concentration (t max ) of the compound was approximately 1 to 1 .5 hours for Tablet Formulations versus 4 hours in case of the nanosuspension.
  • median t max was approximately 1 .75 hours for 2 doses of the 200mg Tablet Formulation versus 2.25 hours in case of the nanosuspension.
  • AUCinf (ngxh/mL) 24,520 (4599) 26,158 (11263) 23,667 (2259) Bioavailability Reference 143.3 137.5 aData represents mean (SD) values
  • the mean ti 2 of the drug compound ranged from about 8 to about 12 h.

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AU2011250909A AU2011250909A1 (en) 2010-05-11 2011-05-11 Pharmaceutical formulations comprising 1 - (beta-D-glucopyranosyl) - 2 -thienylmethylbenzene derivatives as inhibitors of SGLT
LTEP11721616.8T LT2568988T (lt) 2010-05-11 2011-05-11 Farmacinės kompozicijos, apimančios 1-(beta-d-gliukopiranozil)-2-tienilmetilbenzeno darinius kaip sglt inhibitorius
RS20160815A RS55202B1 (sr) 2010-05-11 2011-05-11 Farmaceutske formulacije koje obuhvataju derivate 1-(beta-d-glukopiranozil)-2-tienilmetilbenzena kao sglt inhibitore
EP11721616.8A EP2568988B1 (en) 2010-05-11 2011-05-11 Pharmaceutical formulations comprising 1-(beta-d-glucopyranosyl)-2-thienylmethylbenzene derivatives as inhibitors of sglt
SG2012083184A SG185525A1 (en) 2010-05-11 2011-05-11 Pharmaceutical formulations comprising 1 - (beta-d-glucopyranosyl) - 2 -thienylmethylbenzene derivatives as inhibitors of sglt
KR1020127031880A KR101931209B1 (ko) 2010-05-11 2011-05-11 Sglt의 억제제로서 1-(베타-d-글루코피라노실)-2-티에닐-메틸벤젠 유도체를 포함하는 약학 제형
JP2013510272A JP6227406B2 (ja) 2010-05-11 2011-05-11 ＳＧＬＴの阻害剤としての１−（β−Ｄ−グルコピラノシル）−２−チエニル−メチルベンゼン誘導体を含有する医薬製剤
ES11721616.8T ES2596291T3 (es) 2010-05-11 2011-05-11 Formulaciones farmacéuticas que comprenden derivados de 1-(beta-d-glucopiranosil)-2-tienilmetilbenceno como inhibidores de sglt
SI201130932A SI2568988T1 (sl) 2010-05-11 2011-05-11 Farmacevtske formulacije, obsegajoče 1-(beta-D-glukopiranozil)-2-tienilmetilbenzenske derivate kot inhibitorje SGLT
CA2799204A CA2799204C (en) 2010-05-11 2011-05-11 Pharmaceutical formulations comprising 1 - (beta-d-glucopyranosyl) - 2 -thienylmethylbenzene derivatives as inhibitors of sglt
CN2011800236428A CN102883726A (zh) 2010-05-11 2011-05-11 包含1-(β-D-吡喃葡萄糖基)-2-噻吩基-甲基苯衍生物作为SGLT抑制剂的药物制剂
BR112012028857-1A BR112012028857B1 (pt) 2010-05-11 2011-05-11 Composições farmacêuticas administráveis por via oral que compreendem derivados de 1- (beta-d glucopiranosil)-2-tienil-metilbenzeno como inibidores de sglt
MX2012013090A MX339570B (es) 2010-05-11 2011-05-11 Formulaciones farmaceuticas que comprenden derivados de 1-(beta-d-glucopiranosil)-2-tienil-metilbenceno como inhibidores de transportadores de glucosa dependientes de sodio.
EA201291217A EA022365B1 (ru) 2010-05-11 2011-05-11 Фармацевтические композиции, содержащие производные 1-(бета-d-глюкопиранозил)-2-тиенилметилбензола как ингибиторы нзпг
DK11721616.8T DK2568988T3 (en) 2010-05-11 2011-05-11 Pharmaceutical formulations comprising 1- (BETA-D-glucopyranosyl) -2-THIENYLMETHYLBENZEN derivatives as inhibitors of SGLT
UAA201214097A UA110207C2 (en) 2010-05-11 2011-11-05 Pharmaceutical pill that contains 1- (-d- hlyukopiranozyl) -4-methyl -3- [5- (4-fluorophenyl) -2 inhibitors tiyenilmetyl benzol natriydependent transporter of glucose (nzph)
IL222858A IL222858B (en) 2010-05-11 2012-11-05 Pharmaceutical compositions containing 1-(beta-d-glucopyranosyl)-2-thianylmethylbenzene derivatives as sglt inhibitors
CR20120626A CR20120626A (es) 2010-05-11 2012-12-11 Formulaciones farmacéuticas que comprenden derivados de 1-(beta- D-glucopiranosil)-2-tienilmetil]benceno como inhibidores de los transportadores de glucosa dependientes de sodio (SGLT)
SM201600338T SMT201600338B (it) 2010-05-11 2016-09-26 Formulazioni farmaceutiche comprendenti derivati di1-(beta-d- glucopiranosil)- 2-tienilmetilbenzene come inibitori di sglt
HRP20161231TT HRP20161231T1 (hr) 2010-05-11 2016-09-27 Farmaceutske formulacije koje sadrže derivate 1-(beta-d-glukopiranozil)-2-tienilmetilbenzena kao sglt inhibitore
CY20161101017T CY1118093T1 (el) 2010-05-11 2016-10-12 Φαρμακοτεχνικες μορφες που περιλαμβανουν παραγωγα 1-(bhta-d-γλυκοπυρανοζυλ)-2-θειενυλμεθυλβενζολιου ως αναστολεις sglt

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CN103641822A (zh) * 2013-10-21 2014-03-19 江苏奥赛康药业股份有限公司 一种卡格列净化合物及其药物组合物
CN103641822B (zh) * 2013-10-21 2016-06-08 江苏奥赛康药业股份有限公司 一种卡格列净化合物及其药物组合物
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WO2016030502A1 (en) 2014-08-29 2016-03-03 Sandoz Ag Pharmaceutical compositions comprising canagliflozin

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KR101931209B1 (ko) 2018-12-20
US10617668B2 (en) 2020-04-14
AU2011250909A1 (en) 2012-11-29
AU2017210661A1 (en) 2017-08-24
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JP2013526534A (ja) 2013-06-24
EP2568988A1 (en) 2013-03-20
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MX339570B (es) 2016-05-31
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US20170112806A1 (en) 2017-04-27
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